Given the central role of T-cells in transplant rejection, a common goal among current immunosuppressive therapies is to block T-cell activation and function (Sayegh M H, Turka L A. The role of T-cell costimulatory activation pathways in transplant rejection. N Engl J Med 1998;338(25):1813-21). T-cells require both an antigen-specific (Signal 1) and co-stimulatory signal (Signal 2) for full activation (Lenschow D J, Walunas T L, Bluestone J A. CD28/B7 system of T cell costimulation. Annu Rev Immunol 1996;14:233-58). One of the best-characterized co-stimulatory pathways involves the CD28-CD80/86 (B7-1/2) interaction (Linsley P S, Ledbetter J A. The role of the CD28 receptor during T cell responses to antigen. Annu Rev Immunol 1993; 11:191-212). Cytotoxic T-lymphocyte antigen 4 (CTLA4) binds to CD80/86 with higher avidity than CD28, and is transiently expressed on T-cells following their activation, where it interrupts the interaction between CD28 and CD80/86 (Oosterwegel M A, Greenwald R J, Mandelbrot D A, Lorsbach R B, Sharpe A H. CTLA-4 and T cell activation. Curr Opin Immunol 1999;11(3):294-300.). This creates a negative feedback signal for T-cell activation.
Intervention in this pathway has been previously pursued with CTLA4Ig. CTLA4Ig has been successfully used as a strategy to treat T-cell-mediated autoimmune disorders such as rheumatoid arthritis (Kremer J M, Westhovens R, Leon M, et al. Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig. N Engl J Med 2003;349(20):1907-15) and psoriasis (Abrams J R, Lebwohl M G, Guzzo C A, et al. CTLA4Ig-mediated blockade of T-cell costimulation in patients with psoriasis vulgaris. J Clin Invest 1999; 103(9):1243-52).
LEA29Y has been studied in non-human primate transplant models alone and in combination with other immunosuppressive agents. Christian Larsen et al (C. Larsen, T. Pearson, A. Adams, P. Tso, N. Shirasugi, E. Strobert, D. Anderson, S. Cowan, K. Price, J. Naemura, J. Emswiler, J. Greene, L. A. Turk, J. Bajorath, R. Townsend, D. Hagerty, P. Linsley and R. Peach; Rational Development of LEA29Y (belatacept), a High-Affinity Variant of CTLA4-Ig with Potent Immunosuppressive Properties; American Journal of Transplantation; Vol. 5, Issue 3, March 2005, p. 443) have shown the enhanced immunosuppressive activity of LEA29Y when compared to CTLA4-Ig in a non-human primate model utilized to study renal allograft rejection. LEA29Y was administered intra-operatively (10 mg/kg intravenously), on day 4 (15 mg/kg) and on post-operative days 14, 28, 42, 56 and 70 (20 mg/kg intravenously). CTLA4Ig (16 mg/kg) was administered intra-operatively and on post-operative days 4, 8, 11 and 16. The treatment regimen also included MMF (15 mg/kg bid s.c. on days 0-14, qd on days 15-180), methylprednisolone (subcutaneouse injection according to the following schedule, day 0: 20 mg, day 1: 16 mg, day 3: 8 mg, day 4: 4mg, day 5-14: 3mg, day 15-180: 1 mg) and basiliximab (0.3 gm/kg i.v. on day 0 and 4). Survival of renal allograft recipients treated with LEA29Y was clearly superior to that of a group treated with CTLA4-Ig despite comparable serum concentrations. Control recipients treated with albumin showed a similar median survival time to the group treated with CTLA4-Ig. However, despite ongoing treatment with LEA29Y, all recipients experienced a significant decline in renal function (rise in serum creatinine).
Andrew Adams et al (A. Adams, N. Shirasugi, T. Jones, M. Durham, E. Strobert, S. Cowan, P. Rees, R. Hendrix, K. Price, N. Kenyon, D, Hagerty, R. Townsend, D. Hollenbaugh, T. Pearson and C. Larsen; Development of a Chimeric Anti-CD40 Monoclonal Antibody That Synergizes with LEA29Y to Prolong Islet Allograft Survival; The Journal of Immunology; January 2005; 174; p. 542) have shown that the combination of LEA29Y and Chi220 (a chimeric anti-human CD40 mab) act synergistically in a non-human primate model of pancreatic islet transplantation to prolong allograft survival. LEA29Y was administered intravenously intra-operatively (20 mg/kg);on postoperative days 4, 7 and 14; then every 2 weeks until day 100. Additional doses (20 mg/kg) were administered monthly through 6 months. Four protocols were tested: 1) LEA29Y alone, 2) Chi220 (anti-CD40), 3)LEA29Y combined with Chi220, and 4) LEA29Y combined with anti-CD20.
Andrew Adams et al (A. Adams, N. Shirasugi, M. Durham, E. Strobert, D. Anderson, P. Rees, S. Cowan, H. Xu, Y. Blinder, M. Cheung, D. Hollenbaugh, N. Kenyon, T. Pearson and C. Larsen; Calcineurin Inhibitor-Free CD28 Blockade-Based Protocol Protects Allogeneic Islets in Nonhuman Primates; Diabetes, Vol. 51(2), February 2002, p. 265) have shown that the combination of LEA29Y, rapamycin, and anti-IL-2R mAb significantly prolonged islet allograft survival. in a non-human primate model of pancreatic islet transplantation. LEA29Y was administered intravenously intra-operatively (10 mg/kg) and on postoperative day 4 (15 mg/kg). Additional does of 20 mg/kg were given on postoperative day 14 and every 2 weeks until postoperative day 154.
During 2003 more than 25,000 organs were transplanted in the US. Kidney transplantation represented approximately 60% of the solid organ transplants followed by liver transplants at 21%, heart at 8%, lung at 4% and the remaining 7% represented other organ transplants such as pancreas and intestine. (OPTN/SRTR Annual Report 2004 at www.optn.org)
Renal transplantation is the most effective treatment for end-stage renal disease. It provides improved survival and quality of life (QoL). Maintenance of a functioning renal transplant mandates lifelong immunosuppressive therapy to prevent immune destruction of the graft. Current immunosuppressive regimens yield 1-year survival rates of 89% for cadaveric and 94% for living-donor grafts. Over time, however, there is progressive loss of both subjects and grafts. Five-year survival for cadaveric and living-related donor renal transplants is 66% and 79%, respectively.(United Network for Organ Sharing Renal Transplant Registry 2003 at www.unos.org)
The most common causes of long-term subject and graft loss are cardiovascular disease and chronic allograft nephropathy (CAN), respectively.(L. C. Paul, Chronic allograft nephropathy—A model of impaired repair rom injury? Nephrol Dial Transplant 2000;15:149-151) Paradoxically, the principal therapies for renal transplantation, the calcineurin inhibitors (CNIs), CsA and tacrolimus, directly contribute to long-term allograft loss and subject death, since they are inherently nephrotoxic, and also cause or exacerbate cardiovascular risks, including hypertension, hypercholesterolemia, and diabetes mellitus. Nonetheless, these agents form the cornerstone of all conventional immunosuppressive regimens for renal transplantation.
At present, there are no approved agents that can replace CNIs as cornerstone maintenance immunosuppressant therapy in a broad range of subjects. One agent, sirolimus(rapamycin, Rapamune® from Wyeth/Ayerst), has been approved for use in a CNI-sparing regimen. CNIs, however, must still be used with sirolimus for at least 3 months post-transplantation. More importantly, sirolimus has been approved as a CNI-sparing agent in this setting only for subjects at low to moderate risk of graft loss. Thus, for those at higher risk of graft loss, in whom avoidance of the nephrotoxic effects of CNIs would be of greatest benefit, there is no approved alternative to CNIs.
Therefore, there is an unmet medical need for immunosuppressive agents that can provide acceptable control of the alloimmune response comparable to standard of practice therapies without toxicities that contribute to long-term subject death and graft loss. Ideally, the agent would be useful not only in low-risk subjects, but also in subjects at higher risk of graft loss.